FORMULATION-DEPENDENT BRAIN AND LUNG DISTRIBUTION KINETICS OF PROPOFOL IN RATS

Background: Propofol when administered by brief infusion in a lipid-fr ee formulation has a slower onset, prolonged offset and greater potenc y compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats. Methods: Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations. R esults: Peak propofol plasma concentrations for the lipid-free formula tion were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher th an emulsion formulation. Brain Kp calculated from tissue disposition c urve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively . BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, re spectively. Conclusions: Significant pulmonary sequestration and slow release of propofol into arterial circulation when administered in lip id-free vehicle accounts for the lower peak arterial concentration and sluggish arterial kinetics relative to that observed with the emulsio n formulation. Higher Kp for the lipid-free formulation could explain the higher potency associated with this formulation. BT were independe nt of formulation and correlated with values reported for effect-site equilibration halftime consistent with a distribution mechanism for ph armacologic hysteresis.